title: Cited2 is required for the maintenance of glycolytic metabolism in adult hematopoietic stem cells.
abstract: Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis. At the molecular level, Cited2 deficiency significantly reduced the expression of genes involved in metabolism, such as Pdk2, Pdk4, and lactate dehydrogenases B and D (LDHB and LDHD). Cited2-deficient HSCs also exhibited increased Akt signaling, concomitant with elevated mTORC1 activity and phosphorylation of FoxOs. Further, inhibition of PI3/Akt, but not mTORC1, partially rescued the repression of Pdk4 caused by deletion of Cited2. Altogether, our results suggest that Cited2 is required for the maintenance of adult HSC glycolytic metabolism likely through regulating Pdk2, Pdk4, LDHB, LDHD, and Akt activity.
authors.affiliation: 1 Department of Biochemistry and Comprehensive Cancer Center, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Du
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Fangqiang
authors.initials: F
authors.lastname: Tang
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowitz
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018628:Gene Dosage / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D045022:Lactate Dehydrogenases / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D002867:Chromones; C110087:Cited2 protein, mouse; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D009025:Morpholines; D046912:Multiprotein Complexes; C000631435:Pdk2 protein, mouse; C000631439:Pdk4 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D015534:Trans-Activators; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D045022:Lactate Dehydrogenases; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1; C071195:D-lactate dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005978:Glutathione; D005947:Glucose